Abstract Glioblastoma (GBM) remains a formidable cancer to treat with only anecdotal examples of long-term survivors. Recently, immunotherapy has seen multiple successes against various types of cancer, but several recent clinical trials of this modality in GBM have not been successful. It is evident that two inter-related factors in the complex immunobiology of GBM have thwarted therapeutic efficacy: the existence of multiple immunosuppressive mechanisms and the significant lymphodepletion in the GBM microenvironment. The overarching goal of the Program Project is to address the problem of insufficient T cell activation and marked T cell attenuation in the GBM microenvironment. We will test the overall hypothesis that promotion of CD8+ and CD4+ T cell functionality can overcome the highly immunosuppressive mechanisms of GBM. A corollary to this hypothesis is that preclinical and clinical trials of immunotherapy combinations will provide an effective approach to GBM treatment. We have assembled a highly interactive and interdisciplinary team of 11 investigators in 4 highly integrated Research Projects, supported by 4 Cores. This team (some of whom have been working together for more than two decades) brings deep expertise in immunobiology, neuro- oncology, clinical trials, genomics and computational analyses to mechanistically study these two critical factors. We plan to study how immune checkpoint blockade can be combined with other T cell activating immunotherapies both in a clinical trial (Project 1) and in preclinical mouse models (Project 2). We propose to study novel immunosuppressive pathways in human GBMs based on CD161/ Clec2D (Project 3), IL-27 and endogenous glucocorticoid signaling (Project 4) and understand how these can be overcome to improve the anti-tumor function of CD4 and CD8 effector T cells. Core services will provide sophisticated genomic (Core 1), biocomputational/ biostatistical (Core 2), and mouse modeling/ imaging (Core 3) approaches to these Projects. This Program Project will thus provide significant mechanistic insights into the immunosuppressive microenvironment of GBM, into preclinical avenues of how to activate T cells against these tumors and finally into a novel clinical trial to target personalized GBM neoantigens in humans.